Hemodynamic Induction of Pathologic Remodeling Leading to Intracranial Aneurysms

血流动力学诱导病理重塑导致颅内动脉瘤

• 批准号: 8423044
• 负责人: HUI MENG
• 金额: $ 32.79万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423044
• 关键词: Aneurysm; Angiography; Apoptosis; Bilateral; Biological; Blood flow; Circle of Willis; Dependence; Development; Diagnostic; Dose; Evaluation; Event; Growth; Health; Histology; Intracranial Aneurysm; Ligation; Liquid substance; Location; Maps; Matrix Metalloproteinases; Measurement; Mediating; Modeling; Molecular; Morbidity - disease rate; Morphology; Nitric Oxide; Operative Surgical Procedures; Oryctolagus cuniculus; Pathogenesis; Pathologic; Patients; Peroxonitrite; Play; Prevention strategy; Production; Risk Factors; Role; Rupture; Smooth Muscle Myocytes; Testing; Vascular remodeling; base; cerebrovascular; early onset; hemodynamics; human NOS2A protein; improved; in vivo; mortality; prognostic; research study; response; shear stress

DESCRIPTION (provided by applicant): Little is known about intracranial aneurysm (IA) formation. We submit that specific hemodynamic conditions, not evaluated in prior aneurysm models, are critical for IA formation. Using a rabbit IA model, this project seeks to define these specific hemodynamic conditions responsible for aneurysm initiation and to identify key molecular responses in the pathological vascular remodeling that initiates aneurysms. We hypothesize that: 1) unusual hemodynamics at cerebrovascular bifurcations that is characterized by high wall shear stress (WSS) and wall shear stress gradient (WSSG) induces aneurysmal destructive remodeling, and 2) this pathological response is mediated by localized hemodynamic stimulation of nitric oxide (NO) production and matrix metalloproteinase (MMP) activity. We will evaluate the dose-dependence of this hemodynamic initiation of IAs and use computational fluid dynamics (CFD) to map the initiating hemodynamics. This will define the specific hemodynamic conditions responsible for inducing BT aneurysms, and allow subsequent experiments to examine the biological responses to IA-initiating hemodynamics that precede aneurysm formation. We will then examine hemodynamically induced changes in nitric oxide production and MMP activity during this early period of aneurysm initiation. The roles of NO and MMP in hemodynamic induction of IAs will be tested via pharmacological manipulation of these molecules. Aim 1. Determine specific hemodynamic conditions responsible for flow-induced IA initiation. Aim 2. Determine the role of MMPs in hemodynamic initiation of IAs. Aim 3. Determine the role of iNOS in regulating hemodynamic initiation of IAs. Significance: IA rupture is associated with devastating consequences for patients with high mortality and morbidity. IA formation remains poorly understood. Elucidating the role of specific hemodynamics in IA initiation will pave the way for new mechanistic understandings of IA growth and possibly rupture.

描述（由申请人提供）：对于颅内动脉瘤（IA）的形成知之甚少。我们认为，在先前的动脉瘤模型中未评估的特定血流动力学条件对于 IA 形成至关重要。该项目旨在使用兔 IA 模型来定义导致动脉瘤发生的特定血流动力学条件，并确定引发动脉瘤的病理性血管重塑中的关键分子反应。我们假设：1）以高壁剪切应力（WSS）和壁剪切应力梯度（WSSG）为特征的脑血管分叉处异常血流动力学诱导动脉瘤破坏性重塑，2）这种病理反应是由一氧化氮的局部血流动力学刺激介导的(NO) 产生和基质金属蛋白酶 (MMP) 活性。我们将评估 IAs 的血流动力学启动的剂量依赖性，并使用计算流体动力学 (CFD) 来绘制起始血流动力学图。这将定义导致 BT 动脉瘤的具体血流动力学条件，并允许后续实验检查动脉瘤形成之前对 IA 引发的血流动力学的生物反应。然后，我们将检查在动脉瘤发生的早期阶段血流动力学引起的一氧化氮生成和 MMP 活性的变化。 NO 和 MMP 在 IAs 血流动力学诱导中的作用将通过这些分子的药理学操作进行测试。目标 1. 确定导致血流诱导 IA 启动的具体血流动力学条件。目标 2. 确定 MMP 在 IAs 血流动力学启动中的作用。目标 3. 确定 iNOS 在调节 IAs 血流动力学启动中的作用。意义：IA 破裂会给患者带来毁灭性后果，导致高死亡率和高发病率。 IA 的形成仍然知之甚少。阐明特定血流动力学在 IA 启动中的作用将为对 IA 生长和可能破裂的新机制理解铺平道路。

项目成果

Newtonian viscosity model could overestimate wall shear stress in intracranial aneurysm domes and underestimate rupture risk.

牛顿粘度模型可能高估颅内动脉瘤穹顶的壁剪切应力并低估破裂风险。

• 发表时间: 2012-09
• 作者: Xiang, Jianping;Tremmel, Markus;Kolega, John;Levy, Elad I;Natarajan, Sabareesh K;Meng, Hui
• 通讯作者: Meng, Hui

Utility of pharmacologic provocative neurological testing before embolization of occipital lobe arteriovenous malformations.

枕叶动静脉畸形栓塞前药理学激发神经学测试的效用。

• 发表时间: 2011-09
• 影响因子: 2
• 作者: Tawk, Rabih G;Tummala, Ramachandra P;Memon, Muhammad Z;Siddiqui, Adnan H;Hopkins, L Nelson;Levy, Elad I
• 通讯作者: Levy, Elad I

Salvage Neuroform stent-assisted coiling for recurrent giant aneurysm after waffle-cone treatment.

挽救性 Neuroform 支架辅助弹簧圈栓塞治疗华夫饼锥治疗后复发的巨大动脉瘤。

• 发表时间: 2011-03
• 作者: Hauck, Erik F;Natarajan, Sabareesh K;Hopkins, L Nelson;Levy, Elad I;Siddiqui, Adnan H
• 通讯作者: Siddiqui, Adnan H

Intra- and extraluminal structural and functional venous anomalies in multiple sclerosis, as evidenced by 2 noninvasive imaging techniques.

多发性硬化症的腔内和腔外结构和功能性静脉异常，由 2 种无创成像技术证明。

• 发表时间: 2012-01
• 作者: Dolic, K;Marr, K;Valnarov, V;Dwyer, M G;Carl, E;Karmon, Y;Kennedy, C;Brooks, C;Kilanowski, C;Hunt, K;Siddiqui, A H;Hojnacki, D;Weinstock;Zivadinov, R
• 通讯作者: Zivadinov, R

Is bridging with intravenous thrombolysis of any benefit in endovascular therapy for acute ischemic stroke?

静脉溶栓桥接对急性缺血性卒中的血管内治疗有任何益处吗？

• DOI: 10.1016/j.wneu.2013.01.097
• 发表时间: 2014-09-01
• 期刊: World neurosurgery
• 影响因子: 2
• 作者: T. Kass;T. Kass;O. Kass;O. Kass;M. Mokin;M. Mokin;D. M. Thesier;Parham Yashar;D. Orion;D. Orion;S. Jahshan;S. Jahshan;L. Hopkins;A. Siddiqui;K. Snyder;E. Levy
• 通讯作者: E. Levy